The kindling antagonism model, a modification of standard kindling, involves eliciting epileptiform after discharges (ADs) from two brain sites alternatively. The consistent outcome of this paradigm is a disparity in the seizure development induced from the two sites. One site undergoes a typical kindling progression culminating in a generalized motor seizure. By contrast, kindled seizure development from the other site always halts at one of two points in the kindling process - either between stage 1-2 and stage 3 or between stage 3 and stage 4-5. Our work over the last several years indicates that the kindling antagonism model is directly relevant to the kindling process and operates within the same mechanistic framework as standard kindling. Synthesizing data from our model with data from standard kindling, we have formulated a working hypothesis of the process of seizure propagation during kindled seizure development. This hypothesis deals with both the temporal and spatial organization of kindling. Temporally, we postulate that kindling is a discontinuous, step-wise process which involves two critical transitions from one state of neural organization to another. This project will focus on the first of these transitions. This is defined by the arrested seizure development during kindling antagonism as occurring between stage 1-2 and stage 3. Spatially, we postulate that kindling has a hierarchical, nodal organization. Our data, and that of others, suggest that the piriform cortex (PC) functions as a convergent node for seizure propagation from other forebrain sites. We hypothesize that neural reorganization within this PC node is the basis for the first step in kindled seizure development. We have identified a qualitative change in PC AD characteristics which correlates with this step, and we postulate that this is a marker of PC neural reorganization. This concept of the temporal and spatial architecture of kindled seizure development generates specific, testable predictions concerning the characteristics of kindling which form the basis our specific aims: (1) We predict that the first permanent alteration of seizure susceptibility during kindling will occur at the transition from stage 1-2 to stage 3. In addition, we predict that the alteration of PC AD activity which marks this transition also will be permanent. (2) We predict an asymmetry of transfer of kindled seizure development between the PC and any other forebrain site. This is a consequence of the PC lying "downstream" from all other forebrain sites. (3) We predict that the PC AD change will be a general feature of forebrain kindling. Any forebrain site should induce the same change in the PC AD at the transition between stage 1-2 and stage 3. (4) Forebrain norepinephrine (NE) is known to exert a restraining influence on kindled seizure development. We postulate that NE acts at the site of the PC node, and we predict that depletion of NE confined to the PC will accelerate both the behavioral transition from stage 1-2 and stage 3 and the PC AD change. The overall goal of this project is to provide a framework within which to investigate mechanisms of kindled seizure development. To search for mechanisms, one must know when in the kindling process the critical changes in neural reorganization occur and where in the brain these changes take place.